title: Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study.
abstract: BACKGROUND
  Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing.
  
  
  METHODS
  A total of 27,349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined.
  
  
  RESULTS
  The p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001).
  
  
  CONCLUSIONS
  The p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.
authors.affiliation: Affiliations of authors: Cytomol, Frankfurt, Germany (HI); Laboratoire Cerba, Cergy Pontoise, France (CB); Institute for Pathology, Mannheim, Germany (DS); Center for Pathology and Cytodiagnostics, Cologne, Germany (HG); Hospital del Mar, Barcelona, Spain (FA); Unità Gestionale Screening Regionale, Ospedale Atri, Italy (CA); Labo Lokeren - Campus Riatol, Antwerp, Belgium (JB); Institute Alfred Fournier, Paris, France (RD); North Bristol NHS Trust, Bristol, United Kingdom (KD); Sønderborg Hospital, Sønderborg, Denmark (JH); Acomed statistik, Leipzig, Germany (TK); Institute for Pathology, University of Heidelberg, Heidelberg, Germany (MvkD); Institute for Pathology, Nordhorn, Germany (HHN); University of Barcelona, Barcelona, Spain (LMP-T); European Institute of Oncology, Milan, Italy (MS); Roche mtm laboratories, Mannheim, Germany (SR, RR).
authors.forename: Hans
authors.initials: H
authors.lastname: Ikenberg
authors.forename: Christine
authors.initials: C
authors.lastname: Bergeron
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmidt
authors.forename: Henrik
authors.initials: H
authors.lastname: Griesser
authors.forename: Francisco
authors.initials: F
authors.lastname: Alameda
authors.forename: Claudio
authors.initials: C
authors.lastname: Angeloni
authors.forename: Johannes
authors.initials: J
authors.lastname: Bogers
authors.forename: Roger
authors.initials: R
authors.lastname: Dachez
authors.forename: Karin
authors.initials: K
authors.lastname: Denton
authors.forename: Jalil
authors.initials: J
authors.lastname: Hariri
authors.forename: Thomas
authors.initials: T
authors.lastname: Keller
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.forename: Heinrich H
authors.initials: HH
authors.lastname: Neumann
authors.forename: Luis M
authors.initials: LM
authors.lastname: Puig-Tintore
authors.forename: Mario
authors.initials: M
authors.lastname: Sideri
authors.forename: Susanne
authors.initials: S
authors.lastname: Rehm
authors.forename: Ruediger
authors.initials: R
authors.lastname: Ridder
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002471:Cell Transformation, Neoplastic / Q000737:chemistry; D003127:Colposcopy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003588:Cytopathogenic Effect, Viral; D055088:Early Detection of Cancer / Q000379:methods*; D005060:Europe; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000032:analysis*; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000821:virology; D011446:Prospective Studies; D012017:Referral and Consultation; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000175:diagnosis* / Q000473:pathology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000737:chemistry* / Q000175:diagnosis* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins